Sulpiride
Sulpiride (brand names Dogmatil (HK, SG, PH), Dolmatil (IE, UK), Eglonyl (RU, ZA), Espiride (ZA), Modal (IL), Prometar (UY), Sulpor (UK) and others) is an atypical antipsychotic drug (although some texts have referred to it as a typical antipsychotic4) of the benzamide class used mainly in the treatment of psychosis associated with schizophrenia and major depressive disorder, and sometimes used in low dosage to treat anxiety and mild depression. Sulpiride is commonly used in Europe, Russia and Japan. Levosulpiride is its purified levo-isomer and is sold in India for similar purpose. So far it has not been approved in the United States, Canada and Australia. The drug is chemically and clinically similar to amisulpride. Contents 1 Medical uses 1.1 Pregnancy and lactation 2 Adverse effects 2.1 Contraindications and cautions 2.2 Overdose 3 Synthesis 4 Pharmacology 5 See also 6 References Medical uses Sulpiride's primary use in medicine is in the management of the symptoms of schizophrenia.1 It has been used as both a monotherapy and adjunctive therapy (in case of treatment-resistance) in schizophrenia.156789 It has also been used in the treatment of dysthymia.10 Augmentation with sulpiride has also been tried as a strategy for accelerating antidepressant response in patients with major depressive disorder.11 There is also evidence of its efficacy in treating panic disorder.1213 Pregnancy and lactation Pregnancy: Animal studies did not reveal any embryotoxicity or fetotoxicity, nor did limited human experience. Due to insufficient human data, pregnant women should be treated with sulpiride only if strictly indicated. Additionally, the newborns of treated women should be monitored, because isolated cases of extrapyramidal side effects have been reported.1 Lactation: Sulpiride is found in the milk of lactating women. Since the consequences are unclear, women should not breastfeed during treatment.1 Adverse effects Sulpiride is usually well-tolerated, producing few adverse effects. Their incidences are as follows:1514151617181920 Common (>1%) adverse effectsDizziness Headache Extrapyramidal side effects - Tremor- Dystonia- Akathisia — a sense of inner restlessness that presents itself with the inability to stay still- ParkinsonismSomnolence (not a very prominent adverse effect considering its lack of α1 adrenergic, histamine and muscarinic acetylcholine receptor affinity) Insomnia Weight gain or loss Hyperprolactinemia (elevated plasma levels of the hormone, prolactin which can, in turn lead to sexual dysfunction, galactorrhea, amenorrhea, gynecomastia, etc.) Nausea Vomiting Nasal congestion Anticholinergic adverse effects such as: - Dry mouth- Constipation- Blurred visionImpaired concentration Rare (<1% incidence) adverse effectsTardive dyskinesia — a rare, often permanent movement disorder that, more often than not, results from prolonged treatment with antidopaminergic agents such as antipsychotics. It presents with slow (hence tardive), involuntary, repetitive and purposeless movements that most often affect the facial muscles. Neuroleptic malignant syndrome — a rare, life-threatening complication that results from the use of antidopaminergic agents. Its incidence increases with concomitant use of lithium (medication) salts Blood dyscrasias — rare, sometimes life-threatening complications of the use of a number of different antipsychotics (most notably clozapine) which involves abnormalities in the composition of a person's blood (e.g. having too few white blood cells per unit volume of blood). Examples include: - Agranulocytosis — a significant drop in white blood cell count, leaving individuals wide open to life-threatening opportunistic infections- Neutropenia- Leucopenia- Leukocytosis21Seizures Torsades de pointes Unknown incidence adverse effects includeQTc interval prolongation which can lead to potentially fatal arrhythmias. Cholestatic jaundice22 Elevated liver enzymes Primary biliary cirrhosis23 Allergic reactions Photosensitivity — sensitivity to light Skin rashes Depression Catatonia Palpitations Agitation Diaphoresis — sweating without a precipitating factor (e.g. increased ambient temperature) Hypotension — low blood pressure Hypertension — high blood pressure Venous thromboembolism (probably rare) Contraindications and cautions Contraindications1 Hypersensitivity to sulpiride Pre-existing breast cancer or other prolactin-dependent tumors Phaeochromocytoma Intoxication with other centrally-active drugs Concomitant use of levodopa Acute porphyria Comatose state or CNS depression Bone-marrow suppression Cautions1 Pre-existing Parkinson's Disease Patients below 18 years of age (insufficient clinical data) Pre-existing severe heart disease/bradycardia, or hypokalemia (predisposing to long QT syndrome and severe arrhythmias) Patients with pre-existing epilepsy. Anticonvulsant therapy should be maintained Lithium use — increased risk of neurological side effects of both drugs Overdose Sulpiride has a relatively low order of acute toxicity. Substantial amounts may cause severe but reversible dystonic crises with torticollis, protrusion of the tongue, and/or trismus. In some cases all the classical symptoms typical of severe Parkinson's disease may be noted; in others, over-sedation/coma may occur. The treatment is largely symptomatic. Some or all extrapyramidal reactions may respond to the application of anticholinergic drugs such as biperiden or benzatropine. All patients should be closely monitored for signs of long QT syndrome and severe arrhythmias. Synthesis Sulpiride synthesis: E.L. Engelhardt, Ch.S. Miller, DE 1595915 (1965) E.L. Engelhardt, Ch.S. Miller, DE 1795723 (1965) E.L. Engelhardt, M.L. Thominet, U.S. Patent 3,342,826 (1969) G. Bulteau, J. Acher, U.S. Patent 4,077,976 (1978) F. Mauri, DE 2903891 (1979). Sulpiride can be synthesized from 5-aminosulfosalicylic acid. Methylating this with dimethylsulfate gives 2-methoxy-5-aminosulfonylbenzoic acid, which is transformed into an amide using 2-aminomethyl-1-ethylpyrrolidine as the amine component and carbonyldiimidazole (CDI) as a condensing agent. Pharmacology Sulpiride is a selective antagonist at dopamine D2 and D3 receptors. This action dominates in doses exceeding 600 mg daily. In doses of 600 to 1,600 mg sulpiride shows mild sedating and antipsychotic activity. Its antipsychotic potency compared to chlorpromazine is only 0.2 (1/5). In low doses (in particular 50 to 200 mg daily) its prominent feature is antagonism of presynaptic inhibitory dopamine receptors accounting for some antidepressant activity and a stimulating effect. Therefore, it is in these doses used as a second line antidepressant. Additionally, it alleviates vertigo. The benzamide neuroleptics (including sulpiride, amisulpride, and sultopride) have been shown to activate the endogenous gamma-hydroxybutyrate receptor in vivo at therapeutic concentrations.24 Sulpiride was found in one study in rats to upregulate GHB receptors.25 GHB has neuroleptic properties and it is believed binding to this receptor may contribute to the effects of these neuroleptics. Sulpiride, along with clozapine, has been found to activate DNA demethylation in the brain.26 Protein Binding affinity (Ki nM) towards cloned human receptors27 5-HT1A >10000 D1 >10000 D2 9.8 D3 8.05 D4 54 V3 >10000 See also Atypical antipsychotic Benzamide References 1.^ Jump up to: a b c d e f g h i j k "Sulpiride Tablets 200mg, 400mg (SPC)". electronic Medicines Compendium (eMC). Sanofi. 21 January 2010. Retrieved 19 October 2013. 2.^ Jump up to: a b Bressolle, F; Brès, J; Fauré-Jeantis, A (January 1992). "Absolute bioavailability, rate of absorption, and dose proportionality of sulpiride in humans". Journal of Pharmaceutical Sciences 81 (1): 26–32. doi:10.1002/jps.2600810106. PMID 1619566. 3.Jump up ^ Imondi, AR; Alam, AS; Brennan, JJ; Hagerman, LM (March 1979). "Metabolism of sulpiride in man and Rhesus monkey". Archives Internationales de Pharmacodynamie et de Thérapie 232 (1): 79–91. PMID 96745. 4.Jump up ^ Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8. 5.^ Jump up to: a b Taylor, D; Paton, C; Shitij, K (2012). The Maudsley prescribing guidelines in psychiatry. West Sussex: Wiley-Blackwell. ISBN 978-0-470-97948-8. 6.Jump up ^ Wang, J; Omori, IM; Fenton, M; Soares, B (January 2010). "Sulpiride augmentation for schizophrenia". The Cochrane Database of Systematic Reviews (1): CD008125. doi:10.1002/14651858.CD008125.pub2. 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"Clozapine and sulpiride but not haloperidol or olanzapine activate brain DNA demethylation" (PDF). Proceedings of the National Academy of Sciences of the United States of America 105 (36): 13614–13619. doi:10.1073/pnas.0805493105. PMC 2533238. PMID 18757738. 27.Jump up ^ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 19 October 2013. Category:Typical antipsychotics Category:Benzamides Category:GHB receptor ligands Category:Phenol ethers Category:Pyrrolidines Category:Sulfonamides